Combination therapy using dual inhibitor of c-MET and EGFR and IGF-1R inhibitor

1. A method of treating a cancer in a subject, comprising co-administering a c-Met/EGFR dual inhibitor and an insulin-like growth factor 1 receptor (IGF-1R) inhibitor to the subject,

wherein the c-Met/EGFR dual inhibitor comprises:

1) an anti-c-Met antibody or an antigen-binding fragment thereof, and

2) an anti-EGFR antibody, an antigen-binding fragment thereof, or an anti-EGFR DARPin,

wherein

the anti-c-Met antibody or an antigen-binding fragment thereof recognizes or binds to a polypeptide comprising 5 to 19 contiguous amino acid residues within SEQ ID NO: 71, wherein the polypeptide comprises at least SEQ ID NO: 73, and

the anti-EGFR antibody, an antigen-binding fragment thereof, or an anti-EGFR DARPin comprises:

a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 109, CDR-H2 comprising the amino acid sequence of SEQ ID NO: 110, CDR-H3 comprising the amino acid sequence of SEQ ID NO: 111, CDR-L1 comprising the amino acid sequence of SEQ ID NO: 112, CDR-L2 comprising the amino acid sequence of SEQ ID NO: 113, and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 114,

b) at least one selected from the group consisting of cetuximab, panitumumab, an anti-EGFR antibody or an antigen-binding fragment thereof comprising a heavy chain variable region of SEQ ID NO: 121 and a light chain variable region of SEQ ID NO: 123, and an anti-EGFR antibody or an antigen-binding fragment thereof comprising a heavy chain variable region of SEQ ID NO: 125 and a light chain variable region of SEQ ID NO: 126, or

c) 1 to 10 anti-EGFR DARPin units, each of which is independently selected from the group consisting of SEQ ID NOs: 127 to 130, and

wherein the cancer is gastric cancer or lung cancer that is resistant to treatment with an anti-c-Met antibody or a c-Met/EGFR dual inhibitor in the absence of an IGF-1R inhibitor.

2. The method of claim 1 , wherein

the c-Met/EGFR dual inhibitor and an IGF-1R inhibitor are in a single or mixed formulation, or

each of the c-Met/EGFR dual inhibitor and an IGF-1R inhibitor are administered in separate compositions, simultaneously or sequentially in any order.

3. The method of claim 1 , wherein the anti-c-Met antibody or an antigen-binding fragment thereof comprises:

a CDR-H1 comprising SEQ ID NO: 4; a CDR-H2 comprising SEQ ID NO: 2, SEQ ID NO: 5, or an amino acid sequence comprising 8-19 consecutive amino acids within SEQ ID NO: 2 comprising the 3 rd to 10 th positions of SEQ ID NO: 2; a CDR-H3 comprising SEQ ID NO: 6, SEQ ID NO: 15, SEQ ID NO: 85, or an amino acid sequence comprising 6-13 consecutive amino acids within SEQ ID NO: 85 comprising the 1 st to 6 th positions of the amino acid sequence of SEQ ID NO: 85, a CDR-L1 comprising SEQ ID NO: 7, a CDR-L2 comprising SEQ ID NO: 8, and a CDR-L3 comprising SEQ ID NO: 9, SEQ ID NO: 15, SEQ ID NO: 86, or 9-17 consecutive amino acids within SEQ ID NO: 89 comprising the 1 st to 9 th positions of SEQ ID NO: 89.

4. The method of claim 3 , wherein the anti-c-Met antibody or an antigen-binding fragment thereof comprises:

a heavy chain variable region comprising a CDR-H1 comprising SEQ ID NO: 1, 22, 23, or 24, a CDR-H2 comprising SEQ ID NO: 2, 25, or 26, and a CDR-H3 comprising SEQ ID NO: 3, 27, 28, or 85;

a light chain variable region comprising a CDR-L1 comprising SEQ ID NO: 10, 29, 30, 31, 32, 33, or 106, a CDR-L2 comprising SEQ ID NO: 11, 34, 35, or 36, and a CDR-L3 comprising SEQ ID NO: 12, 13, 14, 15, 16, 37, 86, or 89; or

a combination thereof.

5. The method of claim 3 , wherein the anti-c-Met antibody or an antigen-binding fragment thereof comprises:

a heavy chain variable region comprising SEQ ID NO: 17, 74, 87, 90, 91, 92, 93, or 94;

a light chain variable region comprising SEQ ID NO: 131, 18, 19, 20, 21, 75, 88, 95, 96, 97, 98, 99, or 107; or

a combination thereof.

6. The method of claim 3 , wherein the anti-c-Met antibody comprises:

a heavy chain comprising SEQ ID NO: 62, an amino acid sequence from the 18 th to 462 nd positions of SEQ ID NO: 62, SEQ ID NO: 64, an amino acid sequence from the 18 th to 461 st positions of SEQ ID NO: 64, SEQ ID NO: 66, or an amino acid sequence from the 18th to 460 th positions of SEQ ID NO: 66; and

a light chain comprising SEQ ID NO: 68, an amino acid sequence from the 21 st to 240 th positions of SEQ ID NO: 68, SEQ ID NO: 70, an amino acid sequence from the 21 st to 240 th positions of SEQ ID NO: 70, or SEQ ID NO: 108.

7. The method of claim 1 , wherein the anti-EGFR antibody or an antigen-binding fragment thereof comprises:

a heavy chain variable region comprising SEQ ID NO: 115, 117, 121, or 125;

a light chain variable region comprising SEQ ID NO: 116, 118, 123, or 126; or

a combination thereof.

8. The method of claim 1 , wherein the c-Met/EGFR dual inhibitor comprises:

1) an anti-c-Met antibody and 2) an antigen-binding fragment of an anti-EGFR antibody or an anti-EGFR DARPin comprising 1 to 10 anti-EGFR DARPin units, each of which is independently selected from the group consisting of SEQ ID NOs: 127 to 130,

wherein the antigen-binding fragment of an anti-EGFR antibody or the anti-EGFR DARPin is linked to the C-terminus of the anti-c-Met antibody.

9. The method of claim 1 , wherein the IGF-1R inhibitor comprises at least one selected from the group consisting of an antibody, an aptamer, siRNA, shRNA, microRNA, a small molecule IGF-1R inhibitor, and a pharmaceutically acceptable salt thereof.

10. The method of claim 1 , wherein the IGF-1R inhibitor is at least one selected from the group consisting of linsitinib, NVP-AEW541, GSK1904529A, NVP-ADW742, BMS-536924, figitumumab, cixutumumab, dalotuzumab, R1507, XL-228, INSM-18, BMS-754807, AG-1024, GSK1838705A, PQ 401, and pharmaceutically acceptable salts thereof.

11. The method of claim 1 , wherein the cancer is characterized by overexpression of c-Met.